Nitro-Heterocyclic compounds induce apoptosis-like effects in Leishmania (L). amazonensis promastigotes.

BACKGROUND: Three drugs - pentavalent antimonials, amphotericin B and pentamidine - are currently used for leishmaniasis treatment. They are administered for long periods, only parenterally, and have high cardiac, renal and hepatic toxicities. Therefore, the investigation of new compounds is required. Nitro-heterocyclic derivatives have been used as possible drug candidates to treat diseases caused by trypanosomatids. METHODS: Leishmania (L.) amazonensis promastigotes (MHO/BR/73/M2269), maintained in the Laboratório de Soroepidemiologia - Instituto de Medicina Tropical- USP, were exposed to five nitroheterocyclic derivatives, with differences at phenyl-ring position 4: BSF-C4H9, BSF-H, BSF-NO2, BSF-CH3 and BSF-Cl, for 48 hours. After analyzing viability (MTT assay), we evaluated cellular-morphology activity of compounds by transmission electron microscopy (TEM) and measurement of apoptosis (phosphatidylserine expression) by flow cytometry. RESULTS: EC50 of amphotericin B and BSF-CH3 were 0.50 (M and 0.39 (M respective. Other nitro-heterocyclic compounds presented EC50 higher than amphotericin B. All compounds showed greater AV- and PI-positive expression than amphotericin B at 100 (M, except BSF-NO2. TEM showed complete nuclear disfigurement with 100 (M of BSF-NO2, 25 and 6.25 (M of BSF-H, and 6.25 (M BSF-Cl; presence of vesicles within the flagellar pocket with 25 (M BSF-H; alteration of the kinetoplast with 25 (M BSF-C4H9, 25 (M of BSF-H, 6.25 (M BSF-CH3 and 6.25 (M of BSF-Cl. CONCLUSIONS: Nitro-heterocyclic compounds have shown activity against promastigotes of L. amazonensis, at lower concentrations. However, improvement of compound scaffolds are needed to assist the elucidation of the mechanism of action and to achieve greater activity.

Investigating the structure-activity relationships of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25-30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI') greater than 200, in contrast to the SI' values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease.

BFD-22 a new potential inhibitor of BRAF inhibits the metastasis of B16F10 melanoma cells and simultaneously increased the tumor immunogenicity.

Benzofuroxan is an interesting ring system, which has shown a wide spectrum of biological responses against tumor cell lines. We investigated, herein, the antitumor effects of benzofuroxan derivatives (BFDs) in vitro and in a melanoma mouse model. Cytotoxic effects of twenty-two BFDs were determined by MTT assay. Effects of BFD-22 in apoptosis and cell proliferation were evaluated using Annexin V-FITC/PI and CFSE staining. In addition, the effects in the cell cycle were assessed. Flow cytometry, western blot, and fluorescence microscopy analysis were employed to investigate the apoptosis-related proteins and the BRAF signaling. Cell motility was also exploited through cell invasion and migration assays. Molecular docking approach was performed in order to verify the BFD-22 binding mode into the ATP catalytic site of BRAF kinase. Moreover, the BFD-22 antitumor effects were evaluated in a melanoma murine model using B16F10. BFD-22 was identified as a potential hit against melanoma cells. BFD-22 induced apoptosis and inhibited cell proliferation of B16F10 cells. BFD-22 has suppressed, indeed, the migratory and invasive behavior of B16F10 cells. Cyclin D1 and CDK4 expression were reduced leading to cell cycle arrest at G0/G1 phase. Of note, phosphorylation of BRAF at Ser338 was strongly down-regulated by BFD-22 in B16F10 cells. The accommodation/orientation into the binding site of BRAF was similar of BAY43-9006 (co-crystallized inhibitor of BRAF, sorafenib). Importantly, BFD-22 presented in vivo antimetastatic effects and showed better therapeutic efficacy than sorafenib and taxol. BFD-22 can be considered as a new lead compound and, then, can be helpful for the designing of novel drug candidates to treat melanoma.

Effects of nitro-heterocyclic derivatives against Leishmania (Leishmania) infantum promastigotes and intracellular amastigotes.

Leishmaniasis is an overlooked tropical disease affecting approximately 1 million people in several countries. Clinical manifestation depends on the interaction between Leishmania and the host's immune response. Currently available treatment options for leishmaniasis are limited and induce severe side effects. In this research, we tested nitro-heterocyclic compounds (BSF series) as a new alternative against Leishmania. Its activity was measured in Leishmania (Leishmania) infantum promastigotes and intracellular amastigotes using MTT colorimetric assay. Additionally, we assessed the phosphatidylserine exposure by promastigotes, measured by flow cytometry, as well as nitric oxide production, measured by Griess' method. The nitro-heterocyclic compounds (BSF series) showed activity against L. (L.) infantum promastigotes, inducting the phosphatidylserine exposition by promastigotes, decreasing intracellular amastigotes and increasing oxide nitric production. The selectivity index was more prominent to Leishmania than to macrophages. Compared to amphotericin b, our compounds presented higher IC50, however the selectivity index was more specific to parasite than to amphotericin b. In conclusion, these nitro-heterocyclic compounds showed to be promising as an anti-Leishmania drug, in in vitro studies.

Designing and exploring active N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients.

Chagas disease affects around 8 million people worldwide and its treatment depends on only two nitroheterocyclic drugs, benznidazole (BZD) and nifurtimox (NFX). Both drugs have limited curative power in chronic phase of disease. Nifuroxazide (NF), a nitroheterocyclic drug, was used as lead to design a set of twenty one compounds in order to improve the anti-Trypanosoma cruzi activity. Lipinski's rules were considered in order to support drug-likeness designing. The set of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides was assayed against three T. cruzi strains, which represent the discrete typing units more prevalent in human patients: Y (TcII), Silvio X10 cl1 (TcI), and Bug 2149 cl10 (TcV). All the derivatives, except one, showed enhanced trypanocidal activity against the three strains as compared to BZD. In the Y strain 62% of the compounds were more active than NFX. The most active compound was N'-((5-nitrofuran-2-yl) methylene)biphenyl-4-carbohydrazide (C20), which showed IC50 values of 1.17 ± 0.12 µM; 3.17 ± 0.32 µM; and 1.81 ± 0.18 µM for Y, Silvio X10 cl1, and Bug 2149 cl10 strains, respectively. Cytotoxicity assays with human fibroblast cells have demonstrated high selectivity indices for several compounds. Exploratory data analysis indicated that primarily topological, steric/geometric, and electronic properties have contributed to the discrimination of the set of investigated compounds. The findings can be helpful to drive the designing, and subsequently, the synthesis of additional promising drugs against Chagas disease.

Exploring 5-nitrofuran derivatives against nosocomial pathogens: synthesis, antimicrobial activity and chemometric analysis.

The burden of nosocomial or health care-associated infection (HCAI) is increasing worldwide. According to the World Health Organization (WHO), it is several fold higher in low- and middle-income countries. Considering the multidrug-resistant infections, the development of new and more effective drugs is crucial. Herein, two series (I and II) of 5-nitrofuran derivatives were designed, synthesized and assayed against microorganisms, including Gram-positive and -negative bacteria, and fungi. The pathogens screened was directly related to either the most currently relevant HCAI, or to multidrug-resistant infection caused by MRSA/VRSA strains, for instance. The sets I and II were composed by substituted-[N'-(5-nitrofuran-2-yl)methylene]benzhydrazide and 3-acetyl-5-(substituted-phenyl)-2-(5-nitro-furan-2-yl)-2,3-dihydro-1,3,4-oxadiazole compounds, respectively. The selection of the substituent groups was based upon physicochemical properties, such as hydrophobicity and electronic effect. The compounds have showed better activity against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis. The findings from S. aureus strain, which was more susceptible, were used to investigate the intersamples and intervariables relationships by applying chemometric methods. It is noteworthy that the compound 4-butyl-[N'-(5-nitrofuran-2-yl)methylene]benzhydrazide has showed similar MIC value to vancomycin, which is the reference drug for multidrug-resistant S. aureus infections. Taken the findings together, the 5-nitrofuran derivatives might be indeed considered as promising hits to develop novel antimicrobial drugs to fight against nosocomial infection.

5-Nitro-2-furfuriliden derivatives as potential anti-Trypanosoma cruzi agents: design, synthesis, bioactivity evaluation, cytotoxicity and exploratory data analysis.

The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N'-(5-nitrofuran-2-yl) methylene] benzidrazide (3g; IC50=1.05µM±0.07) and 3-acetyl-5-(4-butylphenyl)-2-(5-nitrofuran-2-yl)-2,3-dihydro,1,3,4-oxadiazole (4g; IC50=8.27µM±0.42), respectively. Also, compound 3g was more active than the standard drugs, benznidazole (IC50=22.69µM±1.96) and nifurtimox (IC50=3.78µM±0.10). Regarding the cytotoxicity assay, the 3g compound presented IC50 value of 28.05µM (SI=26.71) against J774 cells. For the FN1 fibroblast assay, 3g showed IC50 value of 98µM (SI=93.33). On the other hand, compound 4g presented a cytotoxicity value on J774 cells higher than 400µM (SI >48), and for the FN1 cells its IC50 value was 186µM (SI=22.49). Moreover, an exploratory data analysis, which comprises hierarchical cluster (HCA) and principal component analysis (PCA), was carried out and the findings were complementary. The molecular properties that most influenced the compounds' grouping were ClogP and total dipole moment, pointing out the need of a lipophilic/hydrophilic balance in the designing of novel potential anti-T. cruzi molecules.

Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents.

A set of substituted-[N'-(benzofuroxan-5-yl)methylene]benzohydrazides (4a-t), previously designed and synthesized, was experimentally assayed against Trypanosoma cruzi, the etiological agent of Chagas' disease, one of the most neglected tropical diseases. Exploratory data analysis, Hansch approach and VolSurf formalism were applied to aid the ligand-based design of novel anti-T. cruzi agents. The best 2D-QSAR model showed suitable statistical measures [n = 18; s = 0.11; F = 42.19; R(2) = 0.90 and Q(2) = 0.77 (SDEP = 0.15)], and according to the optimum 3D-QSAR model [R(2) = 0.98, Q(2) = 0.93 (SDEP = 0.08)], three latent variables explained 62% of the total variance from original data. Steric and hydrophobic properties were pointed out as the key for biological activity. Based upon the findings, six novel benzofuroxan derivatives (4u-z) were designed, synthesized, and in vitro assayed to perform the QSAR external prediction. Then, the predictability for the both models, 2D-QSAR (Rpred(2) = 0.91) and 3D-QSAR (Rpred(2) = 0.77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3.04 µM).

Polymeric micelles and molecular modeling applied to the development of radiopharmaceuticals

Micelles composed of amphiphilic copolymers linked to a radioactive element are used in nuclear medicine predominantly as a diagnostic application. A relevant advantage of polymeric micelles in aqueous solution is their resulting particle size, which can vary from 10 to 100 nm in diameter. In this review, polymeric micelles labeled with radioisotopes including technetium (99mTc) and indium (111In), and their clinical applications for several diagnostic techniques, such as single photon emission computed tomography (SPECT), gamma-scintigraphy, and nuclear magnetic resonance (NMR), were discussed. Also, micelle use primarily for the diagnosis of lymphatic ducts and sentinel lymph nodes received special attention. Notably, the employment of these diagnostic techniques can be considered a significant tool for functionally exploring body systems as well as investigating molecular pathways involved in the disease process. The use of molecular modeling methodologies and computer-aided drug design strategies can also yield valuable information for the rational design and development of novel radiopharmaceuticals.

Micelas poliméricas compostas de copolímeros ligadas a um elemento radioativo são utilizadas em Medicina Nuclear com aplicação predominantemente diagnóstica. A vantagem relevante da utilização de micelas poliméricas em solução aquosa é o tamanho de suas partículas, as quais podem variar de 10 a 100 nm de diâmetro. Neste trabalho de revisão são apresentadas micelas poliméricas marcadas com radioisotopos, como tecnécio-99m (99mTc) e índio-111 (111In), assim como suas aplicações clínicas em técnicas de diagnóstico como Tomografia por emissão de Fóton Único (Single photon Emission Computed Tomography - SPECT), cintilografia, e Ressonância Magnética Nuclear (RMN). Neste contexto, sua aplicação em diagnóstico de sistema linfático e linfonodo sentinela recebe atenção especial. O emprego de técnicas de diagnóstico pode ser considerado uma ferramenta importante para a exploração de sistemas no organismo humano assim como para a investigação de caminhos moleculares envolvidos nos processos de diversas doenças. O uso de metodologias de modelagem molecular e estratégias de desenvolvimento de fármacos assistidas computacionalmente também pode fornecer informações valiosas para o planejamento e o desenvolvimento racional de novos radiofármacos.

Synthesis, molecular modeling and preliminary biological evaluation of a set of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole as potential antibacterial, anti-Trypanosoma cruzi and antifungal agents.

A series of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives was synthesized and their activity screened in vitro against Staphylococcus aureus, Trypanosoma cruzi, and Candida albicans. The bioactivity was expressed as minimum inhibitory concentration (MIC) for S. aureus strains, and as fifty-percent inhibitory concentration (IC(50)) of parasite population growth for T. cruzi. A molecular modeling approach was performed to establish qualitative relationships regarding the biological data and the compounds' physicochemical properties. The 5-(4-OC(4)H(9)Ph, 5l), and 5-(4-CO(2)CH(3)Ph, 5o) derivatives were the most active compounds for S. aureus ATCC 25923 (MIC=1.95-1.25 µg/mL) and T. cruzi (IC(50)=7.91 µM), respectively. Also, a preliminary evaluation against C. albicans involving some compounds was performed and the 5-(4-CH(3)Ph, 5e) derivative was the most active compound (MIC=3.28-2.95 µg/mL). In this preliminary study, all synthesized 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives were active against all microorganisms tested.

Novel benzofuroxan derivatives against multidrug-resistant Staphylococcus aureus strains: design using Topliss' decision tree, synthesis and biological assay.

The aim of this study was the design of a set of benzofuroxan derivatives as antimicrobial agents exploring the physicochemical properties of the related substituents. Topliss' decision tree approach was applied to select the substituent groups. Hierarchical cluster analysis was also performed to emphasize natural clusters and patterns. The compounds were obtained using two synthetic approaches for reducing the synthetic steps as well as improving the yield. The minimal inhibitory concentration method was employed to evaluate the activity against multidrug-resistant Staphylococcus aureus strains. The most active compound was 4-nitro-3-(trifluoromethyl)[N'-(benzofuroxan-5-yl)methylene]benzhydrazide (MIC range 12.7-11.4 µg/mL), pointing out that the antimicrobial activity was indeed influenced by the hydrophobic and electron-withdrawing property of the substituent groups 3-CF(3) and 4-NO(2), respectively.

Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus.

Molecular modification is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N'-(benzofuroxan-5-yl)methylene]benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological profile. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF(3) substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 microg/mL, and a ClogP value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates.

Molecular modeling studies and in vitro bioactivity evaluation of a set of novel 5-nitro-heterocyclic derivatives as anti-T. cruzi agents.

In this study, in vitro anti-T. cruzi activity assays of nifuroxazide (NX) analogues, such as 5-nitro-2-furfuryliden and 5-nitro-2-theniliden derivatives, were performed. A molecular modeling approach was also carried out to relate the lipophilicity potential (LP) property and biological activity data. The majority of the NX derivatives showed increased anti-T. cruzi activity in comparison to the reference drug, benznidazole (BZN). Additionally, the 5-nitro-2-furfuryliden derivatives presented better pharmacological profile than the 5-nitro-2-theniliden analogues. The LP maps and corresponding ClogP values indicate that there is an optimum lipophilicity value, which must be observed in the design of new potential anti-T. cruzi agents.

Estudos de QSAR-3D em derivados 5-nitro-2-tiofilidênicos com atividade frente a Staphylococcus aureus multi-resistente / 3D QSAR studies of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus

Campos moleculares extraídos de aplicativos utilizados em estudos de QSAR-3D apresentam, em geral, grande número de informações, muitas vezes irrelevantes na expressão da atividade biológica. O programa Volsurf converte as informações presentes em mapas de energia de interação tridimensionais em número reduzido de descritores bidimensionais que se caracterizam como de fácil entendimento e interpretação. Assim, foram avaliados, neste estudo, dezoito derivados 5-nitro-2-tiofilidênicos com atividade antimicrobiana frente a Staphylococcus aureus multi-resistente, correlacionando as características tridimensionais destes ligantes com a referida atividade. Para o desenho e conversão tridimensional dos ligantes foram utilizados os aplicativos Sybyl (Tripos Inc) e CORINA (Molecular Networks GmbH Computerchemie), respectivamente. Os campos de interação molecular foram calculados no programa GRID (Molecular Discovery Ltd). A aplicação do programa Volsurf (Molecular Discovery Ltd) resultou em modelo estatisticamente robusto (r² = 0,93, q² = 0,87) com 48 descritores estruturais, mostrando ser a hidrofobicidade propriedade fundamental no condicionamento da atividade antimicrobiana.

Studies in three-dimensional molecular fields generally contain a large amount of data, some of which are redundant or not relevant. The program Volsurf, a quite fast method, is able to compress the relevant information present in 3D molecular structures into a few easy bidimensional descriptors. This study correlates the antimicrobial activity of eighteen 5-nitro-2-thiophylidene derivatives against multidrug-resistant Staphylococcus aureus with three-dimensional molecular fields of these ligands. For molecular structures sketching and 3D conversion, Sybyl and CORINA programs were used, respectively. The GRID force field was applied to generate the 3D interaction energies. The Volsurf characterization results on significant statistic model with 48 descriptors (r² = 0,93, q²= 0,87), observing a significant influence of hydrophobic properties on antimicrobial activity performance.

A new class of nifuroxazide analogues: synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus.

Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been an increasing problem worldwide since the initial reports over 40 years ago. To examine new drug leads with potential antibacterial activities, 14 p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides were designed, synthesized, and tested against standard and multidrug-resistant S. aureus strains by serial dilution tests. All compounds exhibited significant bacteriostatic activity and some of them also showed bactericidal activity. The results confirmed the potential of this class of compounds as an alternative for the development of selective antimicrobial agents.

Síntese e determinação da atividade antimicrobiana de derivados 5-nitro-2-tiofilidênicos frente a Staphylococcus aureus multi-resistente / Synthesis and determination of antimicrobial activity of 5-nitro-2-thiophylidene derivatives against MRSA

O elevado nível de resistência que cepas de Staphylococcus aureus vêm apresentando aos antibióticos atualmente disponíveis caracteriza-se como grave problema em âmbito mundial e com consequências que beiram à fatalidade. Com a atenção voltada para este fenômeno, quatorze derivados 5-nitro-2-tiofilidênicos foram sintetizados e testados quanto à atividade antimicrobiana frente a cepas padrão (ATCC 25923) e multi-resistente (3SP/R33) de Staphylococcus aureus. Todos os compostos testados apresentaram excelente atividade bacteriostática e, alguns entre eles, atividade bactericida. A 5-nitro-2-tiofilideno-4-acetilbenzidrazida se mostrou como o composto mais ativo com concentração inibitória equivalente a 0,14 mg/mL. A partir dos resultados obtidos evidenciou-se o forte potencial de derivados 5-nitro-2-tiofilidênicos como possível alternativa para o desenvolvimento de novos fármacos com atividade antimicrobiana.

Infection diseases caused by methicillin-resistant Staphylococcus aureus have been an increasing problem worldwide presenting significant morbidity and mortality rates. Thus, fourteen benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides were designed, synthesized and tested against standard (ATCC 25923) and multidrug-resistant strains of Staphylococcus aureus. All compounds exhibited significant bacteriostatic activity and, in such cases, also bactericidal activity, especially the p-COCH3 derivative with MIC = 0.14 mg/mL. The results have demonstrated the potential of synthesized compounds as alternative to the development of selective antimicrobial agents.

Aplicação de estudos de QSAR-2D em derivados 5-nitro-2-tiofilidênicos com atividade antimicrobiana frente a Staphylococcus aureus multi-resistente (MRSA) / 2D QSAR studies of 5-nitro-2-thiophylidene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus (MRSA)

O avanço de estudos de QSAR (Quantitative Structure-Activity Relationships) como método de modificação molecular racionalmente planejada vem se constituindo, nos últimos anos, em alternativa bastante viável para o desenvolvimento de ligantes candidatos potenciais a fármacos. Sendo assim, aliando a excelente aplicabilidade deste método com o fenômeno de multi-resistência bacteriana, realizou-se, neste trabalho, o estudo, em duas dimensões, das relações quantitativas entre a estrutura química e a potência antimicrobiana de 5-nitro-2-tiofilideno benzidrazidas substituídas, considerando faixa de hidrofobicidade ótima pré-determinada experimentalmente. A aplicação da Análise de Hansch/Fujita possibilitou a determinação da influência de descritores estruturais de caráter físico-químico sobre a referida atividade, indicando ser a hidrofobicidade a propriedade de maior impacto no desempenho da atividade biológica analisada. Evidenciou-se, a partir das correlações obtidas, o forte potencial de derivados 5-nitro-2-tiofilidênicos como possível alternativa para o desenvolvimento racional, em nível molecular, de novos fármacos com atividade antimicrobiana

With the constant advance of QSAR (Quantitative Structure-Activity Relationships) studies as molecular modification methodology, a frequent application of this procedure in many science areas was observed. Besides, the rational ligand development for many diseases has been growing in recent years. Thus, in order to ally these medicinal chemistry advances with the necessity to combat the high incidence of antibiotic-resistant microorganisms, the purpose of this study was the 2D-QSAR study of p-substituted 5-nitro-2-thiophylidene derivatives with antimicrobial activity against Staphylococcus aureus, considering hydrophobicity range experimentally determined. The statistical significant correlations obtained by Hansch/Fujita Analysis showed significant influence of hydrophobicity on antimicrobial activity, prove by reasoning the potential of synthesized compounds as a good alternative to the rational development, on molecular level, of selective drugs used to the treatment of infections caused by Staphylococcus aureus multidrug-resistant strains

Experimental and theoretical investigation of the micellar-assisted solubilization of ibuprofen in aqueous media.

Surfactants can be used to increase the solubility of poorly soluble drugs in water and to increase drug bioavailability. In this article, the aqueous solubilization of the nonsteroidal, antiinflammatory drug ibuprofen is studied experimentally and theoretically in micellar solutions of anionic (sodium dodecyl sulfate, SDS), cationic (dodecyltrimethylammonium bromide, DTAB), and nonionic (dodecyl octa(ethylene oxide), C12E8) surfactants possessing the same hydrocarbon "tail" length but differing in their hydrophilic headgroups. We find that, for these three surfactants, the aqueous solubility of ibuprofen increases linearly with increasing surfactant concentration. In particular, we observed a 16-fold increase in the solubility of ibuprofen relative to that in the aqueous buffer upon the addition of 80 mM DTAB and 80 mM C12E8 but only a 5.5-fold solubility increase upon the addition of 80 mM SDS. The highest value of the molar solubilization capacity (chi) was obtained for DTAB (chi = 0.97), followed by C12E8 (chi = 0.72) and finally by SDS (chi = 0.23). A recently developed computer simulation/molecular-thermodynamic modeling approach was extended to predict theoretically the solubilization behavior of the three ibuprofen/surfactant mixtures considered. In this modeling approach, molecular-dynamics (MD) simulations were used to identify which portions of ibuprofen are exposed to water (hydrated) in a micellar environment by simulating a single ibuprofen molecule at an oil/water interface (modeling the micelle core/water interface). On the basis of this input, molecular-thermodynamic modeling was then implemented to predict (i) the micellar composition as a function of surfactant concentration, (ii) the aqueous solubility of ibuprofen as a function of surfactant concentration, and (iii) the molar solubilization capacity (chi). Our theoretical results on the solubility of ibuprofen in aqueous SDS and C12E8 surfactant solutions are in good agreement with the experimental data. The ibuprofen solubility in aqueous DTAB solutions was somewhat overpredicted because of challenges associated with accurately modeling the strong electrostatic interactions between the anionic ibuprofen and the cationic DTAB. Our results indicate that computer simulations of ibuprofen at a flat oil/water interface can be used to obtain accurate information about the hydrated and the unhydrated portions of ibuprofen in a micellar environment. This information can then be used as input to a molecular-thermodynamic model of self-assembly to successfully predict the aqueous solubilization behavior of ibuprofen in the three surfactant systems studied.

Micellar solubilization of drugs.

PURPOSE: Micellar solubilization is a powerful alternative for dissolving hydrophobic drugs in aqueous environments. In this work, we provide an insight into this subject. METHODS: A concise review of surfactants and micelles applications in pharmacy was carried out. RESULTS: Initially, a description of surfactants and aqueous micellar systems is presented. Following, an extensive review on micellar drug solubilization, including both the principles involved on this phenomenon and the work already done regarding solubilization of drugs by micelles is presented. The application of micelles in drug delivery, in order to minimize drug degradation and loss, to prevent harmful side effects, and to increase drug bioavailability, is also presented. Special emphasis is given to the more recent use of polymeric micelles. Finally, we briefly discuss the importance of surfactants and micelles as biological systems models as well as its application in micellar catalysis. CONCLUSIONS: As can be seen from the review presented, the use of micelles in pharmacy is an important tool that finds numerous applications.

Micellar solubilization of ibuprofen - influence of surfactant head groups on the extent of solubilization

An important property of micells with particular significance in pharmacy is their ability to increase the solubility of poorly soluble drugs in water, thus increasing their bioavailability. In this work, the solubilization of ibuprofen (IBU) was studied in micellar solutions of there surfactants possessing the same hydrocarbon tail but different hydrophilic head groups, namely sodium dodecyl sulphate (SDS), dodecyltrimethylammonium bromide (DTAB), and n-dodecyl octa(ethylene oxide) (`C IND. 12´ E`O IND. 8´). The results showed that, irrespective of the surfactant type, the solubility of IBU increased linearly with increasing surfactant concentration, as a consequence of the association between the drug and the micelles...